With a worldwide incidence of 1 in 3000, neurofibromatosis type 1 (NF1) is the most common inherited cancer predisposition syndrome. NF1 is caused by germ line mutations in the NF1 tumor suppressor gene (TSG), which encodes a GTPase activating protein (GAP) called neurofibromin that forms a molecular complex with activated Ras-GTP and negatively regulates Ras signaling by accelerating GTP hydrolysis. NF1, the most common rasopathy, has a propensity to develop neoplastic diseases that progress to aggressive cancers and frequently affect children, adolescents, and young adults. A common feature of NF1-associated neoplasms and malignant tumors is somatic loss of the normal NF1 allele. Importantly, limited epidemiologic data support the hypothesis that patients with NF1 who are cured of a primary cancer are at increased risk of developing treatment-induced secondary neoplasms (SNs). Together, the neoplastic diseases and aggressive malignancies that develop in NF1 are a substantial cause of morbidity and premature mortality. In addition to its role as an initiating mutation in NF1-associated cancers, recent genome-wide sequencing studies uncovered frequent somatic NF1 mutations in glioblastoma, acute myeloid leukemia, adenocarcinoma of the lung, and other sporadic cancers. Importantly, there are currently no mechanism-based therapies for cancers with mutations in genes encoding components of the Ras/GAP molecular switch (KRAS, NRAS, HRAS, and NF1). Thus, our focus will be developing effective higher-quality healthcare delivery options for children, adolescents and young adults with neurofibromatosis (NF) and provide insights that will benefit the entire Ras community. The overall goal of this Developmental and Hyperactive Ras Tumor (DHART) SPORE is to implement effective targeted molecular therapies for neoplasms and cancers by conducting integrated, mechanistically based translational research. The overarching objectives of this highly-qualified, collaborative group are : 1) to evaluate novel therapeutics in validated preclinical models and in the treatment of patients with NF1; 2) to identify risk factors of individuals with NF1 to acquire spontaneous and treatment-associated second malignancies; and 3) to decrease tumor associated morbidity and mortality of patients with NF1. This application draws on the expertise of an accomplished team of clinical investigators, physician/ scientists, and basic researchers with an extensive track record of productive collaborations. This program encompasses four highly integrated projects and three cores. The theme of translational therapeutics informs Projects 1 through 3, and the focus of project 4 exemplifies the role of cancer epidemiology and prevention. State-of-the-art core facilities will inform the patient-oriented cancer therapeutic and prevention aspects of this SPORE by elucidating mutations that contribute to of cancer pathogenesis and by defining biomarkers of drug response and resistance that will inform next generation treatments.